Neurotropic viral disease is an important cause of morbidity and mortality in man. The present application focuses on the protective role of antibodies in herpes simplex virus (HSV) infection, which are among the most prevalent human maladies. Although the most common clinical manifestations of HSV are vesicular eruptions of the skin and mucous membranes, HSV can cause severe keratitis, encephalitis and disseminated illness in the newborn. Furthermore, in immunodepressed patients herpetic manifestations are particularly severe. The emergence of drug-resistant strains of HSV in these patients, after prolonged therapy, is of serious concern both in terms of clinical mangement and of viral ecology. The host immune response plays a crucial role in the recovery from primary HSV infections and in the establishment and maintenance of HSV latency. However, in most individuals natural immunity only provides partial protection from recurrence and reinfection. Therefore, it is of paramount importance to dissect the role of the different components of the immune response in order to understand which aspects are most crucial and whether those components can be boosted to a level sufficient to confer protection. We propose to isolate human monoclonal antibodies from combinatorial Fab libraries and to characterize their mechanisms of action by virology, biochemical, and morphologic methods. With this approach, we have recently generated antibodies against many pathogenic viruses, including HSV. Some of these antibodies displayed potent antiviral activities in both in vitro and in vivo paradigms,. Therefore, we hypothesize that some antibodies generated in the natural immune response can confer a substantial degree of neuroprotection. The proposed research will shed light on the molecular mechanisms behind the protective activity of antibodies against HSV. Such information will be of general importance in understanding the role of the immune system in neurotropic viral infection. In addition, the proposed research will generate antibodies that will be potentially useful in the prophylaxis and treatment of HSV infections. Work on this project has begun with a electron microscopic study on the routes of HSV infection.